Relapsed Mesothelioma Controlled by Checkpoint Inhibition

“The overall survival data are the most remarkable. The tail of the curve could change, but slopes of the curves are consistent with a long-lasting survival effect.”

— Gerard Zalcman, MD

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IN PATIENTS with malignant pleural mesothelioma, combination immunotherapy with two checkpoint inhibitors in the second or third line of treatment extended survival to at least 15 months in the MAPS2 trial,1 sponsored by the Intergroupe Francophone de Cancérologie Thoracique (IFCT) and reported at the 2017 European Society for Medical Oncology (ESMO) Congress by Gerard Zalcman, MD, of the Université Paris-Diderot in France and Past President of IFCT. Study patients received nivolumab (Opdivo), a drug targeting programmed cell death protein 1 (PD-1), alone or combined with the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor ipilimumab (Yervoy).

“The fact that the median overall survival has not been reached in the combination arm suggests it would be more than 15 months,” Dr. Zalcman said. “These overall survival results for second- or third-line treatment of mesothelioma are impressive and comparable with the results of standard chemotherapy in the first-line setting.”

First-line therapy for mesothelioma is pemetrexed (Alimta) and platinum chemotherapy, with or without bevacizumab (Avastin). For patients whose disease progresses after first-line therapy, there is currently no standard-of-care treatment. No drugs tested in this setting have resulted in disease control rates of more than 30%, Dr. Zalcman indicated.

“MAPS2 updated results support the recent National Comprehensive Cancer Network® (NCCN®) panel’s decision to recommend the monotherapy or the combination therapy as options for second- and third-line therapy in relapsing malignant pleural mesothelioma patients,” he added.

Key Findings

THE IFCT-1501 MAPS2 STUDY was a multicenter randomized noncomparative phase II trial in which the primary endpoint was disease control at 12 weeks in each separate arm. It included 125 patients with malignant pleural mesothelioma relapsing after 1 or 2 prior lines of treatment, including a pemetrexed/ platinum doublet. Patients were randomly assigned to receive nivolumab at 3 mg/kg every 2 weeks, alone or with ipilimumab at 1 mg/kg every 6 weeks.

In the first 108 eligible patients, the disease control rate at 12 weeks was 44.4% in the nivolumab arm and 50.0% in the combination arm, as determined by blinded central review. In the intent-to-treat population of 125 patients, these rates were 39.7% and 51.6%, respectively.

“Both the [nivolumab] monotherapy arm and the [ipilimumab/ nivolumab] arm reached their primary endpoint in the second-or third-line treatment of mesothelioma patients, meaningfully increasing the disease control rate at 12 weeks, compared to data from patients in historical series or in previous non-immunotherapy clinical trials,” Dr. Zalcman said.

There were “dramatic responses” and “huge decreases in tumor volume” in both arms, he added. “Long-lasting responses were observed in all histologic subtypes.”

After a median follow-up of 15 months, median progression-free survival was 4.0 months with nivolumab and 5.6 months with the combination. Median overall survival (still immature) was 13.6 months with nivolumab, but it was not reached with the combination after 15 months of median follow-up.

In an exploratory analysis, patients whose tumors contained sarcomatoid histology fared worse with nivolumab alone, incurring a 77% increased risk of death with the single agent but a 43% reduction in risk when treated with the combination. Several other subgroup differences were also demonstrated, patients treated in the third line doing better with the combination arm than with nivolumab alone, whereas patients whose disease progressed beyond 3 months after pemetrexed-based chemotherapy benefited from nivolumab.

“The overall survival data are the most remarkable. The tail of the curve could change, of course, but slopes of the curves are consistent with a long-lasting survival effect,” Dr. Zalcman said. “These overall survival and progression-free survival results support a recent decision by the U.S. Food and Drug Administration to grant orphan drug status to the combination therapy for mesothelioma.”

Quality of Life and PD-L1 Expression

QUALITY OF LIFE AT 12 WEEKS on the Lung Cancer Symptom Scale favored, although not significantly, the monotherapy arm for global, pain, anorexia, and interference items and the combination arm for general and symptom distress items. Long-term and longitudinal quality of life studies (determination of time until definitive deterioration) are pending.

Immunohistochemistry performed on 99 patients revealed that 41% expressed programmed cell death ligand 1 (PD-L1) in 1% of cells or more, and 3 patients had PD-L1 expression ≥ 50% of tumor cells. In the two treatment arms combined, PD-L1 expression ≥ 1% was significantly associated with objective response, whereas PD-L1 expression ≥ 25% significantly predicted response and disease control. PD-L1 expression appeared to favor response and longer overall survival in the nivolumab arm, but it did not influence the overall survival of patients receiving the combination.

Grades 3–5 adverse events occurred in 12.7% of the nivolumab arm and 31.1% of the combination arm, including three deaths in this arm from fulminant hepatitis, encephalitis, and acute kidney failure occuring early in the study course, despite these three grade 5 events. “Toxicity was globally manageable,” he commented. ■

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